INOmax - Product Overview

INOmax is a drug in gas form, the first such drug ever approved by the Food and Drug Administration.

INOmax is administered by inhalation. Nitric oxide, the active substance in INOmax, is a pulmonary vasodilator. INOmax is a gaseous blend of nitric oxide and nitrogen (0.08% and 99.92%, respectively for 800 ppm; 0.01% and 99.99%, respectively for 100 ppm).

Indication
INOmax, in conjunction with ventilatory support and other appropriate agents, is indicated for the treatment of term and near-term (>34 weeks) neonates with hypoxic respiratory failure associated with clinical or echocardiographic evidence of pulmonary hypertension, where it improves oxygenation and reduces the need for extracorporeal membrane oxygenation.

Clinical Pharmacology of INOmax
Nitric oxide is a compound produced by many cells of the body. It relaxes vascular smooth muscle by binding to the heme moiety of cytosolic guanylate cyclase, activating guanylate cyclase and increasing intracellular levels of cyclic guanosine 3',5'- monophosphate, which then leads to vasodilation. When inhaled, nitric oxide produces pulmonary vasodilation.

INOmax appears to increase the partial pressure of arterial oxygen (PaO₂) by dilating pulmonary vessels in better ventilated areas of the lung, redistributing pulmonary blood flow away from lung regions with low ventilation/perfusion (V/Q) ratios toward regions with normal ratios.

Effects on Pulmonary Vascular Tone in PPHN
Persistent pulmonary hypertension of the newborn (PPHN) occurs as a primary developmental defect or as a condition secondary to other diseases such as meconium aspiration syndrome (MAS), pneumonia, sepsis, hyaline membrane disease, congenital diaphragmatic hernia (CDH)*, and pulmonary hypoplasia. In these states, pulmonary vascular resistance (PVR) is high, which results in hypoxemia secondary to right-to-left shunting of blood through the patent ductus arteriosus and foramen ovale. In neonates with PPHN, INOmax improves oxygenation (as indicated by significant increases in PaO₂).

*INOmax is not shown to be effective in patients with CDH.

Key Clinical Trial Findings
The efficacy of INOmax has been investigated in term and near-term newborns with hypoxic respiratory failure resulting from a variety of etiologies. Inhalation of INOmax reduces the oxygenation index (OI=mean airway pressure in cm H₂O x fraction of inspired oxygen concentration [FiO₂] x 100 divided by systemic arterial concentration in mm Hg [PaO₂]) and increases PaO₂.

NINOS Study
The Neonatal Inhaled Nitric Oxide Study (NINOS) group conducted a double-blind, randomized, placebo-controlled, multicenter trial in 235 neonates with hypoxic respiratory failure. The objective of the study was to determine whether inhaled nitric oxide would reduce the occurrence of death and/or initiation of extracorporeal membrane oxygenation (ECMO) in a prospectively defined cohort of term or near-term neonates with hypoxic respiratory failure who were unresponsive to conventional therapy.

Hypoxic respiratory failure was caused by meconium aspiration syndrome (MAS; 49%), pneumonia/sepsis (21%), idiopathic primary pulmonary hypertension of the newborn (PPHN; 17%), or respiratory distress syndrome (RDS; 11%). Infants ²14 days of age (mean, 1.7 days) with a mean PaO₂ of 46 mm Hg and a mean oxygenation index (OI) of 43 cm H₂O / mm Hg were initially randomized to receive 100% O₂ with (n=114) or without (n=121) 20 ppm nitric oxide for up to 14 days.

Response to study drug was defined as a change from baseline in PaO₂ 30 minutes after starting treatment (full response = >20 mm Hg, partial = 10-20 mm Hg, no response = <10 mm Hg). Neonates with a less than full response were evaluated for a response to 80 ppm nitric oxide or control gas. The primary results from the NINOS study are presented in Table 1.

Table 1 Summary of Clinical Results from NINOS Study
	Control (n=121)	NO (n=114)	P value
Death or ECMO*, †	77 (64%)	52 (46%)	0.006
Death	20 (17%)	16 (14%)	0.60
ECMO	66 (55%)	44 (39%)	0.014
* Extracorporeal membrane oxygenation † Death or need for ECMO was the study's primary end point

Although the incidence of death by 120 days of age was similar in both groups (NO, 14%; control, 17%), significantly fewer infants in the nitric oxide group required ECMO compared with controls (39% vs. 55%, p = 0.014). The combined incidence of death and/or initiation of ECMO showed a significant advantage for the nitric oxide treated group (46% vs. 64%, p = 0.006). The nitric oxide group also had significantly greater increases in PaO₂ and greater decreases in the OI and the alveolar-arterial oxygen gradient than the control group (p<0.001 for all parameters). Significantly more patients had at least a partial response to the initial administration of study drug in the nitric oxide group (66%) than the control group (26%, p<0.001).

Significantly fewer neonates treated with INOmax received ECMO

Neonatal Inhaled Nitric Oxide Study (NINOS)^1,3

INOmax significantly improves oxygenation, as measured by partial pressure of arterial oxygenation and oxygenation index^1-3

Significantly greater PaO₂ increases in 30 minutes³

Of the 125 infants who did not respond to 20 ppm nitric oxide or control, similar percentages of NO-treated (18%) and control (20%) patients had at least a partial response to 80 ppm nitric oxide for inhalation or control drug, suggesting a lack of additional benefit for the higher dose of nitric oxide. No infant had study drug discontinued for toxicity. Inhaled nitric oxide had no detectable effect on mortality. The adverse events collected in the NINOS trial occurred at similar incidence rates in both treatment groups (See ADVERSE REACTIONS section of Prescribing Information by clicking the link at the bottom of this page).

Follow-up exams were performed at 18-24 months for the infants enrolled in this trial. In the infants with available follow-up, the two treatment groups were similar with respect to their mental, motor, audiologic, or neurologic evaluations.

CINRGI study
The CINRGI (pronounced “synergy”) study was a double-blind, randomized, placebo-controlled, multicenter trial of 186 term and near-term neonates with pulmonary hypertension and hypoxic respiratory failure. The primary objective of the study was to determine whether INOmax would reduce the receipt of ECMO in these patients. Hypoxic respiratory failure was caused by MAS (35%), idiopathic PPHN (30%), pneumonia/sepsis (24%), or RDS (8%). Patients with a mean PaO₂ of 54 mm Hg and a mean OI of 44 cm H₂O / mm Hg were randomly assigned to receive either 20 ppm INOmax (n=97) or nitrogen gas (placebo; n=89) in addition to their ventilatory support. Patients who exhibited a PaO₂ >60 mm Hg and a pH < 7.55 were weaned to 5 ppm INOmax or placebo. The primary results from the CINRGI study are presented in Table 2.

Table 2 Summary of Clinical Results from CINRGI Study
	Placebo	INOmax	P value
ECMO*,†	51/89 (57%)	30/97 (31%)	<0.001
Death	5/89 (6%)	3/97 (3%)	0.48
* Extracorporeal membrane oxygenation † ECMO was the study's primary end point

Significantly fewer neonates treated with INOmax received ECMO

Clinical Inhaled Nitric Oxide Research Group (CINRGI)¹

Significantly fewer neonates in the INOmax group required ECMO compared to the control group (31% vs. 57%, p<0.001). While the number of deaths were similar in both groups (INOmax, 3%; placebo, 6%), the combined incidence of death and/or receipt of ECMO was decreased in the INOmax group (33% vs. 58%, p<0.001). In addition, the INOmax group had significantly improved oxygenation as measured by PaO₂, OI, and alveolar-arterial gradient (p<0.001 for all parameters). Of the 97 patients treated with INOmax, 2 (2%) were withdrawn from study drug due to methemoglobin levels >4%. The frequency and number of adverse events reported were similar in the two study groups (See the ADVERSE REACTIONS section of Prescribing Information by clicking the link at the bottom of this page).

Important safety information about INOmax

•	INOmax should not be used in the treatment of neonates known to be dependent upon right-to-left shunting of blood.¹
•	Methemoglobinemia is a dose-dependent side effect of inhaled nitric oxide therapy. Therefore, methemoglobin levels should be monitored during INOmax administration. Caution should be used when administering INOmax with other drugs that may cause methemoglobinemia regardless of their route of administration.¹
•	Nitrogen dioxide (NO₂) forms rapidly in gas mixtures containing nitric oxide and oxygen. NO₂ formed in this way may cause airway inflammation and damage.¹
•	INOmax must be administered through a system which does not cause excessive generation of NO₂ and that monitors for NO, NO₂, and FiO₂.¹
•	Abrupt discontinuation of INOmax therapy may lead to worsening of PaO₂ and increasing pulmonary artery pressure (PAP). Deterioration in oxygenation and elevation in PAP may also occur in patients with no apparent response to INOmax.¹

Adverse events from the CINRGI study with an incidence of at least 5% in patients receiving INOmax, and that were more common in INOmax patients compared with placebo patients.¹

•	6-month follow-up data of patients in controlled studies who received INOmax (n=278) or placebo (n=212) found no evidence of an adverse event of treatment on the need for rehospitalization, special medical services, pulmonary disease, or neurologic sequelae.¹

References
1. INOmax® [package insert]. Clinton, NJ: INO Therapeutics, Inc.; 1999. Revised 2006.
2. Clark RH, Kuesser TJ, Walker MW, et al. Clinical Inhaled Nitric Oxide Research Group (CINRGI). Low dose nitric oxide therapy for persistent pulmonary hypertension of the newborn. N Engl J Med. 2000;342:469-474.
3. Neonatal Inhaled Nitric Oxide Study Group (NINOS). Inhaled nitric oxide in full-term and nearly full-term infants with hypoxic respiratory failure. N Engl J Med. 1997;336:597-604.
4. Data on file, INO Therapeutics LLC.

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